Synthesis of steroids



United States Patent This invention relates to the synthesis of steroids and, more particularly, to the provision of a new steroid, 12,21 cyclo A nor 145,170: pregna 3,12(21)- diene-2,15,20-trione, having the formula The new steroid of this invention is a physiologically active substance that possesses anti-androgenic activity (i.e., it inhibits the action of anhydrogens).

The compound is prepared by heating 12,15-diketo-A- norprogesterone with a strong base, such as sodium methoxide, as more fully described in the following example:

EXAMPLE (a) Preparation of 1213,] Sa-dihydroxy-Amorpmgesterone A 150 gallon fermentor containing 112 g. of A-norprogesterone in media containing corn steep liquor, NH H PO CaCO yeast extract, dextrose and soy bean oil is inoculated with a culture of Colletotrichum linicolae NCTC (National Collection of Type Cultures) No. 1194 (obtainable from the Commonwealth Mycological Institute, Kew, Surrey, England). After thirtysix hours, the whole broth is filtered and the filtrate extracted with one-half volume of chloroform in a Podbielniak extractor. The chloroform solution is washed with water, dried over sodium sulfate and evaporated to a crystalline mass. Trituration with 3 l000 ml. of hexane removes color and oil. The crude dry weight is 101.6 g. This material is recrystallized from acetone/ hexane to give 67 g. of product which contains 11a,15adihydroxy-A-norprogesterone and 12fi,15a-dihydroxynorprogesterone.

The separation of these components is accomplished 3,324,184 Patented June 6, 1967 by column chromatography on 2300 g. alumina. Elution of the column with chloroform and continued elution with chloroform/methanol 200:1 and :1 gives 10.3 g. of 12,8,15a-dihydroxy-A-norprogesterone.

(b) Preparalion of 12,]5-diketo-A-norprogesterone mg. of 12,9,l5a-dihydroxy-A-norprogesterone is dissolved in 20 ml. of acetone. 0.5 ml. of 8 N chromic acid reagent is added and the solution held at room temperature for one hour. The excess reagent is destroyed with isopropanol, water added and the solution extracted with chloroform. The chloroform phase is washed with sodium carbonate, water, then dried over sodium sulfate and evaporated giving a crude product of 89 mg. Recrystallization from acetone/hexane gives 63 mg. of 12,.15-diketo-A-norprogesterone.

( (1) Preparation of 12,21-cycl0-A-n0r-14a,1 7fi-pregna- 3,12 (2] -diene-2,Z5,20-trione A solution of 768 mg. of 12,15-diketo-A-norprogesterone in 152 ml. of 0.1 N sodium methoxide is refluxed under nitrogen for 1 hour. The green solution is then cooled, neutralized with dilute acetic acid, diluted with 100 ml. of water, and partially evaporated in vacuo. It is then diluted further with 100 ml. of water and eX- tracted with chloroform. The chloroform extract is washed with water and evaporated. Crystallization of the residue from acetone-hexane gives about 343 mg. of 12,21 cyclo A nor 14,8,17a pregna 3,12(21)- diene-2,15,20-trione, having a melting point about 254- 256 C., [a1 -217 '(chloroform),

A313; 233 m (6, 28,400), ARE 5.77, 5.85, 5.91 (sh), 6.15 73 4.14 s, 21-11 4.20 s, 3-H), 8.48 s, 18-Me), 8.76 (S, 19-Me).

Analysis.-Calcd. for C H O (310.38): C, 77.33; H, 7.14. Found: C, 77.65; H, 7.48.

The invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. 12,21- cyclo A nor -14,8,17u pregna 3,12(21)- diene-2,15,20-trione.

2. A process for preparing 12,2l-cyclo-A-nor-14B,17apregna-3,12(2l)-diene-2,15,20-trione, which comprises heating 12,15-diketo-A-norprogesterone with sodium methoxide.

No references cited.

LEON ZITVER, Primary Examiner. M. JACOB, Assistant Examiner. 

2. A PROCESS FOR PREPARING 12,21-CYCLO-A-NOR-14B,17APREGNA-3,12(21)-DIENE-2,15,20-TRIONE, WHICH COMPRISES HEATING 12,15-DIKETO-A-NORPROGESTERONE WITH SODIUM METHOXIDE. 